# Circadian Rhythms and Cocaine Use Disorder

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $456,033

## Abstract

PROJECT SUMMARY
Despite decades of critical research into its biological mechanisms and treatment approaches, Substance Use
Disorder (SUD) persists as a major world health problem. In the last few years, approximately 21 million people
required SUD treatment. Still, recent years have seen dramatic increases in the number of overdose deaths due
to heroin, prescription opioids, and cocaine. Interestingly, there is some work that suggests a circadian rhythm
and robust time-of-day shifts in the function of specific receptors and neurotransmitter systems that are routinely
implicated in drug abuse vulnerability and relapse. For example, diurnal (i.e., light/dark) variation has been
observed in mesolimbic dopamine (DA) system, including rhythms in extracellular DA tone, DA transporter levels/
function, and DA receptor function. Moreover, research in both humans and animal models has observed that
level of drug taking and seeking can vary throughout the day. While published work demonstrates regulators of
diurnal variation in DA tone and tone regulators, there is a large gap in research dedicated to understanding
regulators of diurnal variation and circadian rhythms in subsecond, phasic DA release. This is particularly
important given the role of phasic DA release in reinforcement learning, motivation, and goal-directed behavior
that is altered in SUD. Moreover, little work has been dedicated to understanding how the function of intrinsic
modulators of phasic DA release, such as acetylcholine (ACh) from striatal cholinergic interneurons, vary across
time-of-day. Therefore, the overall objective of this research proposal is to determine the circadian diurnal
differences in rapid DA and ACh signaling and how these rhythms are mechanistically linked to changes in
motivated behavior, cocaine/reward seeking, and cue-reward associations. Our central hypothesis is that there
are times-of-day that individuals will exhibit increased sensitivity to reward- and cocaine-associated cues that
can lead to cocaine seeking, which are mediated by time-of-day variations in the cholinergic interneuron
modulation of rapid DA signaling. Specific Aim 1 will use rat models to investigate diurnal variation in 1) incentive
motivational value towards reward-associated cues using pavlovian conditioned approach task, 2) the degree to
which cues increase instrumental responding using a pavlovian-instrumental transfer task, and 3) the subjective
value of cocaine and corresponding motivation to take cocaine. We will also examine the magnitude of both DA
and ACh signaling in the nucleus accumbens (NAc) core using ex vivo fast scan cyclic voltammetry across the
light / dark cycles. Specific Aims 2 and 3 will utilize voltammetry, fiber photometry, and optogenetics in freely-
behaving rats to measure diurnal modulation of phasic DA and CIN activity across a 24-hour day and define a
circuit specific mechanism for differences in motivated behavior, cocaine seeking, and corresponding magnitu...

## Key facts

- **NIH application ID:** 10298986
- **Project number:** 1R01DA052460-01A1
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Mark J Ferris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $456,033
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298986

## Citation

> US National Institutes of Health, RePORTER application 10298986, Circadian Rhythms and Cocaine Use Disorder (1R01DA052460-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10298986. Licensed CC0.

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